This invention relates to a pharmacological composition and method that provides for surface anti-thrombotic activity of endothelial cells and without exerting any appreciable amount of blood anticoagulation. This composition is preferably used for patients susceptible to or suffering from a cardiovascular disorder or disease, and more particularly, but not by way of limitation, to a formulation with enhanced absorption characteristics for preventing and treating atherosclerosis, arteriosclerosis, congestive heart failure, arterial stenosis, cardiac cell hypertrophy, thrombogenicity, myocardial infarction, cerebrovascular ischemia, peripheral vascular ischemia, angina pectoris, hypertension or endothelial dysfunction, without appreciably increasing the patient""s risk of hemorrhaging, either internal or as a result of an external injury.
Cardiovascular disorders and diseases resulting from cell surface thrombosis, and their associated complications are a principal cause of disabilities and deaths of individuals in the world. For example, in recent years more than 500,000 deaths have occurred annually in the United States alone as a result of coronary artery disease, and an additional 1,200,000 patients have been hospitalized for myocardial ischemia and infarction.
There has been significant and extensive research for effective long term treatment for disorders and diseases of the heart and arteries, such as atherosclerosis, arteriosclerosis, congestive heart failure, angina pectoris, and other diseases associated with the cardiovascular system. However, present treatments for such disorders are short term treatments such as administration of vasodilators, angioplasty, and by pass surgery. These treatments have serious shortcomings in long term effectiveness, thus they have met with general disapproval due to the risks associated with them. The use of vasodilator drugs and mechanical treatments for acute and chronic occlusive vascular diseases of the heart central and peripheral vascular systems have to date been ineffective for favorable long-term results and do not treat the underlying molecular processes causal for the diseases.
The focus of current treatment methods is to react to potentially immediate danger to one""s life. Even the prescription of xe2x80x9cstatinxe2x80x9d drugs such as Lovastatin, were originally designed to treat patients with significant risk of present danger of heart attacks due to high cholesterol levels. The only reason the long term risks associated with taking cholesterol reducing agents or xe2x80x9cstatinsxe2x80x9d was justified because of the immediate danger the high cholesterol levels presented to a patient. Almost all of the current treatment methods focus on reducing and/or eliminating the occlusion of larger arteries and none take into consideration that, for example, over 75% of fatal heart attacks are in patients with no present signs of significantly occluded arteries. The insertion of stents and such mechanical devices into larger arteries to prevent occlusion are only temporary procedures. Thus, the result is that myocardial infarction is temporarily delayed. However, such procedures merely postpone eventual myocardial infarction as the underlying molecular processes continue untreated. The result of the current treatments has had minimal impact on the long-term processes of atherosclerosis. For example a significant number of patients who receive angioplasty have a repeat coronary event within three to five years. The cost associated with these treatments, both in terms of medical expenses as well as fatalities and lost productivity, is enormous.
Furthermore, the rationale for using statin drugs to lower plasma cholesterol fails to explain why coronary heart attacks generally occur in individuals with non-critical blockages and why blockages do not occur in capillaries or veins. When used, statin drugs reduce the risk of a recurrent coronary event, only by 30 to 40%.
The rationale for vasoactive drugs is to reduce blood pressure by acting directly or indirectly on vascular and/or cardiac smooth muscle, thereby decreasing vascular resistance to flow. Such drugs do not treat initial cause of elevated pressure and abnormal flow. Rather, they seek to reduce the resulting effect of the disorder. Such drugs activate the sympathetic nervous system by way of a baroreceptor reflex to produce an increased heart rate and force of myocardial contraction, which are not beneficial or desirable effects. Other side effects for such drugs include headache, heart palpitations, anxiety, mild depression, myocardial infarction, congestive heart failure, fatigue and weakness. Further, pharmacological effect is not specific in its effect on the initial molecular cause of the disease activity, and treats a limited spectrum of effects in the diseases, which are dependent on several factors.
None of these treatment methods is directed towards the underlying disease processes, the molecular causes of the disease or disorders, or towards restoring the structure and function of the blood vessels to levels that reduce or eliminate the danger posed by cardiovascular diseases. There is no treatment to reduce the level of obstruction in arteries that are not severely occluded or to enhance the arteries inherent ability to resist thrombus formation, leaving these patients still at significant risk of a heart attack.
In view of the foregoing, there is a significant need for a pharmacological composition and method that is directed towards treating the underlying cardiovascular disease process, and towards restoring the structure and improving the functions of the blood vessel cells and in particular the function-structure properties of the endothelium which lines all blood vessels and the heart.
It is an objective of the present invention to provide a treatment, which is directed to preventing and minimizing dysfunctional atomic and molecular interactions within the human cellular matrix or cellular environment, which lead to cardiovascular disease and atherosclerosis.
It is another objective of the present invention to provide a treatment that is directed to retarding adverse consequences of free radicals generated in human cellular matrix. It is also another objective of the present invention to stimulate an increased production of nitric oxide within human cellular matrix or cellular environment.
It is yet another objective of the present invention treatment of cardiovascular diseases, in particular cell surface based thrombosis, without appreciably increasing blood anticoagulation activity in patients.
The present invention provides for a method and composition for treatment of the mammalian cellular environment for the prevention of endothelial dysfunction comprising the step of administering to a patient a therapeutically-effective amount of Rhamnan Sulphate, or its physiologically acceptable salts, in therapeutic proportions.
The dose of Rhamnan Sulphate administered to the patient is equivalent to between approximately 2,000 IU and 200,000 IU of heparin activity daily. Alternatively, the dose of Rhamnan Sulphate is approximately 7.5 mg/kg as a single dose or repeated daily, or optionally substituted for by its functional analogs, in predetermined amounts to achieve the desired effects. A physiological acceptable salt of Rhamnan Sulphate is formed by covalently bonding L-Arginine to the Rhamnan Sulphate.
The invention also describes a method for inducing cell surface anti-thrombotic activity in endothelial cells for treatment of cardiovascular disease without appreciably increasing the risk of hemorrhaging in patients, comprising the step of oral administration to a patient a therapeutically-effective amount of Rhamnan Sulphate. The present invention uses a therapeutically-effective amount of Rhamnan Sulphate or their respective physiologically-acceptable salts or functional analogs, to provide a patient with protection against endothelial dysfunction, without appreciably increasing the patient""s risk of internal or external hemorrhaging.
An advantage of the method and composition of the invention is that it possesses extremely potent antithrombotic activity and other inhibitory effects on cell surface coagulation assembly and activity for thrombus inhibition.
Another advantage of the described composition is that there is less peptide residual in extracting the composition from plant cells as compared to heparin from animal cells. Hence, it is less allergic reaction prone and has fewer immunogenic properties.
Yet another advantage is that since Rhamnan Sulphate is from plant cells, it has no potential for the transmission of potentially lethal and serious prion diseases such as mad cow disease.
Another advantage is that Rhamnan Sulphate has no potential for activating Platelet Factor IV and resulting in immune complex destruction of platelets as seen with heparin administration.
Finally, another advantage of Rhamnan Sulphate is that it is a functional substitute for heparin in applications requiring systemic anticoagulant activity such as dialysis, bypass surgery, and polymer tube coatings and devices for use in mammals and humans.